The cavity of cyclodextrins (CDs) can form host-guest (HG) complexes with a number of substrates including charged and neutral molecular species.(1'2) However, formation of CD-substrate complexes can involve processes other than simple binding to the cavity. Derivatized CDs have been prepared which indicate that the appended groups can participate in the CD-substrate complexation. Furthermore, substrates of molecular size larger than the CD cavity may bind outside the cavity. Recent work from our group demonstrated that the charge-transfer state (the A* state) of p-dimethylaminobenzonitrile (DMABN) binds outside of beta- cyclodextrin (beta-CD), while the neutral excited state (the B* state) of the same molecule forms a HG complex. This finding stresses the fact that the HG complex is not necessarily the more stable one and that solvation effects and the charge distribution of the substrate play an important role in the binding processes involving weak interactions. It is apparent from this information that although CDs can regarded as very simple hosts, their mode of interaction with substrates cannot be known or predicted a priori. The present research is designed under the premise that the information and methods developed investigating CD-substrate systems could be extended to further the understanding of interactions involving ligands and biomedically relevant proteins. It should be noted that due to the conformational variability of proteins, it is very difficult to measure the protein-ligand binding constants over large temperature ranges. Also, as a consequence of the great variety of surface residues, the number of non-specific interactions which can lead to protein-ligand binding can be very large. The proposed study represents a unique approach to obtain information concerning the most basic parameters which could affect complex formation. We will establish the nature of the interactions between a substrate and the CD cavity and compare these interactions with those which occur with the relatively simple surface of this molecule. Such comparisons should represent an important step towards understanding the mechanisms leading to complex formation and as a consequence provide useful information concerning the more complicated interactions in biological molecules. The formation of a H-G complex by a substrate may alter its radiative lifetime, excited state energy, thermal and photochemical reactivity and we can monitor those changes to derive information about the nature of these interactions. Establishing the nature of a wide variety of CD- substrate complexes could be important in predicting the stability of substrate-enzyme complexes using computer models and for the design of potent enzyme inhibitors.